Provided methods of obtaining a plurality of T cell receptors specifically recognizing a target tumor antigen peptide from an individual that has clinically benefitted from an immunotherapy, such as Multiple Antigen Specific Cell Therapy. Also provided tumor-specific TCRs, engineered immune cells expressing the TCRs and methods of treating a disease using the engineered immune cells.

The present disclosure relates to cells capable of co-expressing T cell receptors (“TCR”) together with membrane-bound IL-15 polypeptides and/or CD8 polypeptides and the use thereof in adoptive cellular therapy. The present disclosure further provides for modified IL-15, IL-15Rα, IL-15/IL-15Rα fusion polypeptide, and IL-15Rα/IL-15 fusion polypeptide sequences, vectors, and associated methods of making and using the same. The present disclosure further provides for modified CD8 sequences, vectors, and associated methods of making and using the same.

Expansion of cytotoxic T lymphocytes (CTLs) is a crucial step in almost all cancer immunotherapeutic methods. Current techniques for expansion of tumor-reactive CTLs present major limitations. The present invention comprises a novel method to effectively produce and expand tumor-activated CTLs using high-voltage pulsed electric fields. Tumor cells were subjected to high-frequency irreversible electroporation (HFIRE) with various electric field magnitudes and pulse widths, or irreversible electroporation (IRE). The treated tumor cells were subsequently cocultured with CD8+ cytotoxic T cells along with antigen-presenting cells. Tumor-activated CTLs can be produced and expanded when exposed to treated tumor cells. The activated CTLs produced with the present invention could be used for clinical applications with the goal of targeting and eliminating tumors.

Provided herein, inter alia, are methods and compositions for treating or preventing graft-versus-host disease. The methods include administering to a tissue transplant recipient a composition comprising a donor-derived regulatory T cell.

Composition and methods for ex vivo expansion of natural killer (NK) cells, and methods for cell-based cancer immunotherapy are disclosed. Leukemic cell-derived dendritic cells and anti-PD-L1 antibodies, and certain embodiments with addition of PBMCs are used for in vivo administration for cancer treatment. Leukemic cell-derived dendritic cells and anti-PD-L1 antibodies are also used for ex vivo expansion of NK cells.

Provided herein, inter alia, are compositions and methods for reprogramming immune cells for treating or preventing immune disorders. The methods include contacting immune cells with antigens, and administering the resultant immune cells to a subject who has an immune disorder.

Disclosed are compositions of matter, protocols and procedures useful for preventing/treatment ovarian failure. In one embodiment cytokines promoting anti-inflammatory/regenerative activity are administered systemically, or locally in order to preventing ovarian degeneration/fibrosis. In one embodiment low dose interleukin-2 is administered either alone or with adjuvant cytokines to induce an increase in FoxP3 expressing CD4 cells. In some embodiments in vivo generation of FoxP3 expressing CD4 cells is associated with stimulation of intra-ovarian angiogenesis and prevention of fibrosis.

Provided are methods for isolating T-cells with T cell receptors (TCRs) optimized for reactivity to specific peptides and decreased cross-reactivity to non-target peptides. Advantageously, TCRs of the invention can be optimized to target cancer antigens and peptides while having reducing reactivity to healthy cells. Methods of the invention utilize a novel combination of culturing conditions that increase T-cell activation and allow for validation of TCR activity. Culturing conditions of the invention further reduce culturing times generally needed to achieve expanded reactive T-cells. Because of the robust nature of the activation and validation conditions of the present invention, variants of identified TCRs can also be optimized and validated for their response to peptides, including cancer peptides.

Provided are methods for isolating T-cells with T cell receptors (TCRs) optimized for reactivity to specific peptides and decreased cross-reactivity to non-target peptides. Advantageously, TCRs of the invention can be optimized to target cancer antigens and peptides while having reducing reactivity to healthy cells. Methods of the invention utilize a novel combination of culturing conditions that increase T-cell activation and allow for validation of TCR activity. Culturing conditions of the invention further reduce culturing times generally needed to achieve expanded reactive T-cells. Because of the robust nature of the activation and validation conditions of the present invention, variants of identified TCRs can also be optimized and validated for their response to peptides, including cancer peptides.

The generation of antigen specific T cells by controlled ex vivo induction or expansion can provide highly specific and beneficial T cell therapies. The present disclosure provides T cell manufacturing methods and therapeutic T cell compositions which can be used for treating subjects with cancer and other conditions, diseases and disorders personal antigen specific T cell therapy.